Luminal epithelial cells integrate variable responses to aging into stereotypical changes that underlie breast cancer susceptibility

Sep 21, 2026

Uploaded by Aurelia

Aging effects differ between individual cells yet often appear as stereotyped tissue-level phenotypes, raising questions about how cellular variability translates into common aging outcomes. This study tests the hypothesis that aging impacts on lineage maintenance increase susceptibility to cancer initiation. Transcriptomic analyses compare primary luminal epithelial and myoepithelial cells from women under 30 versus over 55, showing increased transcriptional variance, loss of lineage fidelity, and luminal-enriched directional chromatin regulation. Machine learning identifies luminal aging signals predictive of breast cancer subtype.

LanguageEnglish

CategoryResearch & Report

FormatPDF

Pages54

Reading Time2 h 16 min

AccessFree to download

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RESEARCH ARTICLE *For correspondence: [rwsayaman@gmail.com](rwsayaman@gmail.com) (RWS); [mlabarge@coh.org](mlabarge@coh.org) (MALaB) †These authors contributed equally to this work Present address: ‡University of California, San Francisco, Department of Laboratory Medicine, Helen Diller Family Comprehensive Cancer Center, San Francisco, United States; §Rajiv Gandhi Centre for Biotechnology, Thycaud, India; \#Arab American University, Department of Biology and Biochemistry, Faculty of Medicine, Ramallah, Palestine Competing interest: The authors declare that no competing interests exist. Funding: See page 35 Preprinted: 23 September 2022 Received: 29 December 2023 Accepted: 08 November 2024 Published: 15 November 2024 Reviewing Editor: Richard M White, University of Oxford, United Kingdom This is an open-access article, free of all copyright, and may be freely reproduced, distributed, transmitted, modified, built upon, or otherwise used by anyone for any lawful purpose. The work is made available under the Creative Commons CC0 public domain dedication. Luminal epithelial cells integrate variable responses to aging into stereotypical changes that underlie breast cancer susceptibility Rosalyn W Sayaman1,2,3,4*†‡, Masaru Miyano1,2†, Eric G Carlson1,5, Parijat Senapati6§, Arrianna Zirbes1,5, Sundus F Shalabi1,5\#, Michael E Todhunter1,2, Victoria E Seewaldt1, Susan L Neuhausen1, Martha R Stampfer4, Dustin E Schones6, Mark A LaBarge1,2,7* 1City of Hope, Department of Population Sciences, Beckman Research Institute, Duarte, United States; 2City of Hope, Center for Cancer and Aging, Beckman Research Institute, Duarte, United States; 3City of Hope, Cancer Metabolism Training Program, Beckman Research Institute, Duarte, United States; 4 Lawrence Berkeley National Lab, Biological Sciences and Engineering, Berkeley, United States; 5City of Hope, Irell and Manella Graduate School of Biological Sciences, Duarte, United States; 6City of Hope, Department of Diabetes Complications and Metabolism, Beckman Research Institute, Duarte, United States; 7Center for Cancer Biomarkers Research, University of Bergen, Bergen, Norway Abstract Effects from aging in single cells are heterogenous, whereas at the organ-and tissuelevels aging phenotypes tend to appear as stereotypical changes. The mammary epithelium is abilayer of two major phenotypically and functionally distinct cell lineages: luminal epithelial and myoepithelial cells. Mammary luminal epithelia exhibit substantial stereotypical changes with age that merit attention because these cells are the putative cells-of-origin for breast cancers. We hypothesize that effects from aging that impinge upon maintenance of lineage fidelity increase susceptibility to cancer initiation. We generated and analyzed transcriptomes from primary luminal epithelial and myoepithelial cells from younger <30 (y)ears old and older >55 y women. In addition to age-dependent directional changes in gene expression, we observed increased transcriptional variance with age that contributed to genome-wide loss of lineage fidelity. Age-dependent variant responses were common to both lineages, whereas directional changes were almost exclusively detected in luminal epithelia and involved altered regulation of chromatin and genome organizers such as SATB1 . Epithelial expression variance of gap junction protein GJB6 increased with age, and modulation of GJB6 expression in heterochronous co-cultures revealed that it provided a communication conduit from myoepithelial cells that drove directional change in luminal cells. Age-dependent luminal transcriptomes comprised a prominent signal that could be detected in bulk tissue during aging and transition into cancers. A machine learning classifier based on luminalspecific aging distinguished normal from cancer tissue and was highly predictive of breast cancer subtype. We speculate that luminal epithelia are the ultimate site of integration of the v

FAQs

What biological question does the study address about aging and breast cancer?

It examines how variable cellular aging responses can be integrated into stereotypical changes that increase breast cancer susceptibility.

What cell types and age groups were analyzed?

Primary luminal epithelial and myoepithelial cells were analyzed from younger (<30 years) and older (>55 years) women.

How does the study link aging-driven cellular changes to cancer risk?

It finds increased transcriptional variance with age, loss of lineage fidelity, and luminal-enriched directional transcriptome signals that can be detected in bulk tissue and predict cancer subtype using machine learning.

Sep 21, 2026

Uploaded by Aurelia